Ingestive Behaviors 33. Introduction. Page 1. control and story lines. (a review of general endocrinology) Integration (or the basic reflex arc model)

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1 Ingestive Behaviors 33 (a review of general endocrinology) A neuroendocrine system: components, a reflex arc, the endocrine system, the AN, endocrine / nervous systems as afferents and efferents, the theoretical comparator or integrator unit, membrane potential, transcription factors and integrators, crosstalk at a subcellular level as a regulatory paradigm lements involved in the neuroendocrine of food intake, the hypothalamic PVN, M and POA as integration centers, discussion of other integrated neuroendocrine systems (stress and temperature regulation linked to stress and food intake) and of obesity and as a story of circles, intersecting circles, intersecting circles, intersecting... Introduction afferent story line sensor and story lines Integration (or the basic reflex arc model) integrator center negative feedback story line basic diagram for a system as that present in a refrigerator efferent story line effector Page 1

2 Physiological ndocrinology Circles within circles nergy production, utilization and storage Maintenance of internal environment Growth and development Reproduction The endocrine system is a communication system involved in homeostatic of life. It acts through its hormones which four main basic processes A basic reflex arc model has organization levels, structure / function, Physiological ndocrinology Circles within circles The basic reflex arc model is based on the neuronal components of a reflex arc Page 2

3 Theoretical elements Circles within circles variable under (t C / F) thermostat (set point) t C / F detector (feedback) comparator common language error signal (on/off) engine (amplifier) hypothalamus set point long loop negative feedback N T C A P short and ultrashort negative feedbacks hierarchies: gonadal TARGT adrenal thyroid others FINAL NDOCRIN FFCT Refrigerators are regulated with similar components to that of an endocrine sytem Negative feedback is gonadal hierarchy C adrenal hierarchy C thyroid hierarchy C 2 P4 receptor comp. Cortisol. receptor comp. T3 receptor comp. Circles within circles N TC GnRH AP CRH AP TRH AP gonad adrenal thyroid 2 / P4 cortisol T3 - T4 The basic reflex arc model is shown by the various endocrine hierarchies Page 3

4 Negative feedback is Recovery of the HPA axis after Cushing syndrome or chronic dexamethasone As a rule, brain elements of a feedback regulation are usually the most important Negative feedback is PTH and Vit.D increase blood Ca while Calcitonin decreases it blood Ca decrease calcium receptor parathyroid gland PTH PTH receptor Gs / AC Gq / PLC Vit. D PTH absorption resorption blood intestine Ca bone secretion formation Calcitonin Calcitonin reabsorption filtration PTH kidney bone formation, osteoblast kidney, Ca filtration intestine, Ca secretion bone resorption, osteoclast kidney, Ca reabsorption, Vit. D intestine, Ca absorption Calcitonin receptor Gs / AC Calcitonin thyroid gland calcium receptor blood Ca increas e An exception to the rule stated in the previous slide is that of Ca homeostasis Page 4

5 Negative feedback is HPA axis is involved only under disease conditions A partial exception to the rule stated in the previous slides is RA-aldosterone system Neural systems Neuronal elements in the communication operation within a system Page 5

6 Neural systems The action potential as the neuronal communication unit ndocrine systems The hormone as the endocrine communication unit Page 6

7 AN P pre post Ach Ne Integrator () negative feedback afferent / efferent communication pathways might be neurogenic and / or endocrine pathways Feedback signals are effector signals which are recognized as inputs How an integrator might work A background for a neurogenic integrator comes from the function of PP and IPP Page 7

8 How an integrator might work A background for both neurogenic and endocrine integrators comes from camp How an integrator might work R Na / K pump camp ----> PKA ----> channel / enzyme AC Protein synthesis teroid + R ----> R 5 3 HR XX1 1 mrna R DNA additional transcription factor A background for both neurogenic and endocrine integrators comes from steroids Page 8

9 How an integrator might work A background for neurogenic / endocrine integrators comes from AgII and cross-talk How an integrator might work PVN POA M The PVN, the M and the POA are the three main CN integrators discussed in lectures Page 9

10 Hypothalamic hypometabolism PVN M POA T3-T4 (low) TH (low / normal) TRH mrna (low) UC proteins (low) TRH-induced TH release (high) TRH release (low) inhibits TH release Insulin (low) Glucagon (high) Cortisol (high) pinephrine (high) LH/FH (low) Leptin (low) Cas, NPY, amh, ARN thermogenesis (low) energy expenditure (low) Tertiary hypometabolic states (hibernation, startvation) show how integrators work The neuroendocrine of food intake also shows how integrators work and fail Page 10

11 PYY Ghrelin Insulin CCK Leptin A recent article in Time magazine targeted for a general audience about this topic Hypothetical regulatory system for maintaining constancy of adipose mass by monitoring the mass of stored fat. Adjustments in energy intake and expenditure are made to maintain constancy. Green arrows (+) denote increase; red arrows (-) denote decrease. Ultimately how you look will result from your integrator s balancing act Page 11

12 Overall regulation of energy balance. Ghrelin is the only known hunger signal arising from gut. All other input from the GI tract signal satiety. Leptin and insulin are the principal adiposity signals. Ultimately how you look will result from your integrator s balancing act Major routes of communication in the regulation of energy balance. Cross talk between the hypothalamus and the dorsal vagal complex integrates input from adiposity and satiety signals. The dorsal vagal complex includes the area postrema, the nucleus of the tractus solitarius, and the dorsal motor nucleus of the vagus. IL-6 = interleukin 6; CRH = corticotropin releasing hormone; MCH = melanin concentrating hormone; OXM = oxyntomodulin; PYY = peptide YY; CCK = cholecystokinin; GLP-1 = glucagon-like peptide-1; PPP = pancreatic polypeptide. Page 12

13 Inputs to the central network Glucose availability glucose sensitive neurons in brain stem (NT, AP), hypothalamus (VMH-DMH,PVN) and hepato-portal circulation (to NT). ensory stimuli to NT, PBN and cortex. Body energy stores leptin in ARC- VMH The PVN is a main central integrator involved in neuroendocrine of food intake Long and short term inputs e.g. Leptin inhibits food intake Long - term Insulin, Leptin cortisol, T3-T4, GH / IGF1 hort - term Glucose, Proteins and Fats GI volume and GI peptides The PVN is a main central integrator involved in neuroendocrine of food intake Page 13

14 Leptin and food intake Kg Women leptin Men body weight body fat years of age leptin body weight fasting pair-fed leptin % body fat Clinical and experimental data suggesting that leptin plays a metabolic role Leptin and food intake Parabiotic experiment of Coleman lack satiaty factor normal ob/ob ob/ob resistant to satiaty factor db/db db/db e.g. leptin inhibits food intake and stimulates energy expenditure db/db ob/ob db/db ob/ob Leptin is secreted from the adipocytes and signals the brain about their status Page 14

15 Leptin and food intake e.g. leptin inhibits food intake and stimulates energy expenditure Leptin acts centrally (e.g. HPG, HPT, HPA) & peripherally (e.g. immune, angiogenesis) Leptin and food intake e.g. leptin inhibits food intake and stimulates energy expenditure Leptin has a variety of central and peripheral effects, as outlined in this slide Page 15

16 Leptin and food intake Long form of the leptin receptor (Ob-Rb)mediates leptin actions Koletsky rats having a point mutation (Ob-Rb) are obese ----> BBB e.g. leptin inhibits food intake and stimulates energy expenditure CN receptors for leptin are located in the AR/M (3V) and in the area postrema (4V) Leptin and food intake e.g. leptin inhibits food intake and stimulates energy expenditure Leptin receptors in AR/M are located in NPY/AGRP & POMC/CART containing cells Page 16

17 Leptin and food intake leptin inhibits food intake & stimulates energy expenditure BB stimulate inhibit Neuronal = N Blood - Born = BB DMH PVN POMC, amh, CART, CRH NPY, AGRP, MCH, Orexin BB PBN AP LH DMN BB VMH A ARC M NT CN receptors for leptin are located in the AR/M (3V) and in the area postrema (4V) N Leptin and food intake leptin inhibits food intake & stimulates energy expenditure stimulate POMC, amh, CART, CRH inhibit NPY, AGRP, MCH, Orexin Catecholamines Na + (NT-PVN) ; DA - (LH-PVN) erotonin 5HT1b - (LH-PVN) Histamine GABA H2 - (VMH-PVN) GABAa + (VMH) and - (LH) NPY and Galanin NPY + ; GAL + (ARC-PVN) CRH and CCK CRH - (A-VMH) ; CCK - (NT-PVN) amh, AGRP and GLP1 amh - ; AGRP + (ARC-PVN-MC4R) GLP1 - (NT-PVN) Orexins and MCH Orexin + ; MCH + (LH-PVN) CART CART - (ARC-DMH, NT) Main central pathways regulating food intake Page 17

18 Leptin and food intake Main central pathways regulating the effect of leptin on food intake Leptin and food intake chematic drawing of the relationship between the principal neurons in the arcuate nuclei that fuel consumption and energy utilization to each other and to their up- and downstream effectors. NPY = neuropeptide Y; NPYR = NPY receptor; AGRP = agouti related peptide; MCR4 = melanocortin receptor 4 (MH receptor); MCH = melanin concentrating hormone; -MH = melanocyte stimulating hormone; CART = cocaine and amphetamine related transcript; GABA = gama amino butyric acid; GnRH = gonadotropin releasing hormone; CRH = corticotropin releasing hormone; TRH = thyrotropin releasing hormone; GHRH = growth hormone releasing hormone. Main central pathways regulating the effect of leptin on food intake Page 18

19 Integrator s balancing act Circles intersecting circles Obesity & are only the extremes of the central integrators playfield Integrator s balancing act Changes in energy expenditure after increase or decrease of body weight. Thirteen normal subjects were overfed a defined diet until their body weight increased by 10%. leven normal subjects were underfed until their body weight decreased by 10%. Both groups were then fed just enough to maintain their new weights for two weeks, at which time energy expenditure and lean body mass were measured. To diet or not to diet. That is the question. Page 19